1. Field of the Invention
The present invention relates generally to synergistic combinations of guanosine analog reverse transcriptase inhibitors (GA-RTI), such as abacavir, with potent inosine monophosphate dehydrogenase (IMPDH) inhibitors such as mycophenolic acid, its derivatives and related compounds, pharmaceutical compositions comprising such combinations and therapeutic methods comprising administering such combinations to patients in need thereof, for treating a viral infection, such as an HIV-1 infection.
2. Description of the Related Art
Acquired Immunodeficiency Syndrome (AIDS) is an immunosuppressive or immunodestructive disease that predisposes subjects to fatal opportunistic infections. Characteristically, AIDS is associated with a progressive depletion of T-cells. Human immunodeficiency virus (HIV) has been reproducibly isolated from patients with AIDS or with the symptoms that frequently precede AIDS. HIV is cytopathic and preferentially infects and destroys T-cells, and it is now generally recognized that HIV is the etiological agent of AIDS.
Anti-HIV therapies have generally taken the approach of inhibiting or blocking functions that are specific to HIV, e.g., functions that are necessary in the viral lifecycle but are not part of the host cell""s metabolism, for example specific viral protease inhibition, viral RNA-to-DNA transcription.
HIV is a retrovirus and consequently employs the viral enzyme reverse transcriptase to transcribe its single-stranded RNA into double-stranded DNA competent for integration and the completion of the viral lifecycle. Interruption of this step prevents viral replication. Potent and selective inhibitors of reverse transcriptase have been identified and shown to have utility in anti-retroviral pharmaceutical compositions. These reverse transcriptase inhibitors (RTI""s) generally fall into two broad classes, nucleoside analogs such as zidovudine and lamivudine, and the non-nucleoside reverse transcriptase inhibitors (NNRTI""s) such as Efavirenz ((S)-6-chloro-4-(cyclopropylethynyl)-1,4-dihydro-4-(trifluoromethyl)-2H-3,1-benzoxazine-2-one, Sustiva(copyright), Dupont Pharmaceuticals).
Nucleoside analog RTI""s can be further classified based on the nucleoside that they mimic. For example, the well-known RTI""s zidovudine, 3xe2x80x2-azido-3xe2x80x2-deoxythymidine (Retrovir(copyright), formerly called azidothymidine (AZT), Glaxo Wellcome, Inc.), stavudine (2xe2x80x2,3xe2x80x2-dihydro-3xe2x80x2-deoxythymidine, d4T, Zerit(copyright)), Bristol-Myers-Squibb Corp.), and lamivudine, (2R,cis)4-amino-1-(2-hydroxymethyl-1,3-oxathiolan-5-yl)-(1H)-pyrimidin-2-one (3TC, Epivir(copyright), Glaxo-Wellcome) are pyrimidine nucleoside analogs that have been widely used alone and in combination in anti-retroviral pharmaceutical applications.
Purine nucleoside analogs have been identified that have useful reverse transcriptase inhibitory activity as well. Didanosine (2xe2x80x2,3xe2x80x2-dideoxyinosine, DDI, Videx(copyright), Bristol-Myers-Squibb Corp.) is an adenosine nucleoside analog that is used in RTI pharmaceutical compositions.
Recently the first guanosine nucleoside analogs that are potent reverse transcriptase inhibitors (xe2x80x9cGA-RTI""sxe2x80x9d) have been identified. Such GA-RTI""s are described, e.g., in U.S. Pat. No. 5,089,500, xe2x80x9cTherapeutic Nucleosides,xe2x80x9d issued Feb. 18, 1992; U.S. Pat. No. 5,034,394, entitled xe2x80x9cTherapeutic Nucleosides,xe2x80x9d issued Jul. 23, 1991; and U.S. Pat. No. 5,087,697, same title, issued Feb. 11, 1992, the disclosures of all of which are hereby incorporated herein by reference in their respective entireties.
Abacavir (Ziagen(trademark); (1 S,cis)4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol sulfate, Glaxo Wellcome, Inc.) is the first clinically available guanosine analog HIV-1 reverse transcriptase inhibitor. The most potent nucleoside analog yet developed, when studied in the setting of monotherapy abacavir resulted in a 1.55 log drop in plasma HIV-1 RNA (Ziagen package insert. Glaxo Wellcome, Inc., Research Triangle Park, N.C.). Other guanosine analogs are in development, e.g., DAPD (1-xcex2-D-2,6-diaminopurine dioxolane; Triangle Pharmaceuticals, Inc., Research Triangle Park, N.C.).
HIV is wholly dependent on cellular deoxyribonucleoside triphosphate (dNTP) for the transcription of viral single-stranded RNA into double-stranded DNA competent for integration and the completion of the viral lifecycle. Viral dependence on host factors has been exploited as a novel approach to inhibit HIV-1 replication (e.g., Johns D G; Gao W Y, xe2x80x9cSelective depletion of DNA precursors: an evolving strategy for potentiation of dideoxynucleoside activity against human immunodeficiency virus.xe2x80x9d Biochem Pharmacol. May 15, 1998 ;55(10):1551-6).
An unfortunate aspect of HIV infection is the ability of the virus to rapidly mutate and the frequency with which new strains arise with resistance to various drug therapies. Consequently, there is a need to develop new therapeutic approaches to anti-HIV treatment and. in particular, approaches that combine more than one viral target entity. Further, there is a need for approaches that combine one or more viral targets with inhibition of a host cell function or reduction of a host cell substance or factor which enables viral replication.
The present invention provides such a novel combination approach.
The present invention takes advantage of a surprising and powerful newly discovered synergistic effect between guanosine analog reverse transcriptase inhibitors (xe2x80x9cGA-RTIxe2x80x9d) and potent inhibitors of the enzyme inosine monophosphate dehydrogenase (IMPDH), such as mycophenolic acid and analogs and their pharmaceutically acceptable salts, derivatives, and prodrugs (collectively, xe2x80x9cmycophenolatesxe2x80x9d), to provide novel combinations having utility in the treatment of viral infections, especially in treating HIV infection.
The present invention provides therapeutic compositions comprising synergistically effective amounts of at least one GA-RTI compound and at least one IMPDH inhibitor, such as a mycophenolate compound.
In another aspect the present invention provides a novel composition for treating viral infection, such as a retroviral infection, comprising a pharmaceutically acceptable carrier and a synergistic combination of at least one GA-RTI compound and at least one IMPDH inhibitor, such as a mycophenolate compound.
In another aspect the present invention provides a novel method for treating or preventing a viral infection, such as an HIV infection, comprising administering to a subject in need thereof a therapeutically effective amount of a combination of at least one GA-RTI compound with at least one IMPDH inhibitor, such as a mycophenolate compound.
In preferred embodiments, the synergistic combinations of the invention comprise at least one compound selected from GA-RTI compounds of the general formula: 
where
R3 represents hydrogen or C1-C6 alkyl;
R6 represents C3-8 cycloalkyl;
R7 represents hydrogen or branched or straight chain C1-6 alkyl;
or a pharmaceutically acceptable derivative thereof; in combination with at least one mycophenolate compound selected from mycophenolic acid, and pharmaceutically acceptable salts, derivatives, analogs and prodrugs of mycophenolic acid, which has the formula: 
and where the GA-RTI compound(s) and the mycophenolate compound(s) are combined in amounts and proportions to yield a therapeutically effective composition for treatment of disease states mediated by retroviral infection.
The synergistic combinations of the present invention may further comprise pharmaceutical carriers.